Zoledronic acid is a bisphosphonic acid, which is an inhibitor of osteoclastic bone resorption. Zoledronic acid, designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid is marketed in the U.S. under the name Zometa® (zoledronic acid for injection). Zometa® is available in vials as a sterile powder for reconstitution for intravenous infusion. The prescribing information for Zometa® states that each vial of Zometa® contains 4.264 mg of zoledronic acid monohydrate (corresponding to 4 mg zoledronic acid on an anhydrous basis).
U.S. Pat. No. 4,939,130 discloses a method for making substituted alkanediphosphonic acids. Example 10 describes a method for making zoledronic acid. In this example, at the end of the reaction, the product, which is recrystallized from water, has a melting point of 239° C. with decomposition. However, repetition of the procedure described in Example 10 (which requires stirring under reflux imidazol-1-ylacetic acid hydrochloride and phosphoric acid in chlorobenzene) did not lead to zoledronic acid; instead, the starting material was collected at the end of the reaction. Moreover, the last step of crystallization could not be repeated exactly since the detailed experimental parameters are not given (different cooling regimes, for instance, can produce different polymorphs when crystallized in the same solvent).
In the paper Drugs of the future 2000, 25(3): 259-268 the following forms of Zoledronate are listed:
1) Zoledronic acid disodium salt tetrahydrate CAS No. 165800-07-7
2) Zoledronic acid magnesium salt CAS No. 157432-59-2
3) Zoledronic acid zinc salt CAS No. 157432-58-1
4) Zoledronic acid disodium salt anhydrous CAS No. 131654-46-1
5) Zoledronic acid anhydrous CAS No. 118072-93-8
6) Zoledronic acid monohydrate CAS No. 165800-06-6
It is also disclosed in the paper that the free acid has a melting point of 239° C. with decomposition, and the disodium salt dihydrate has a melting point of 291-293° C. with decomposition. However, the paper does not describe any procedure to obtain the forms mentioned therein, nor does it give any additional data by which they can be identified. Moreover, there is nothing in the literature that discloses polymorphs or different crystal forms of zoledronic acid.
The solid state physical properties of a compound can be influenced by controlling the conditions under which the compounds are obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
These practical physical characteristics are determined by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray diffraction (PXRD), solid state 13C NMR spectrometry and infrared spectrometry.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. The invention provides for new polymorphic forms of zoledronic acid and zoledronate sodium, and for amorphous zoledronate sodium.